Levemir
Levemir is Novo Nordisk A/S's worldwide brand name for insulin detemir, a long-lasting insulin analog that lasts up to 24 hours in humans. Its chief benefits according to Novo are a "peakless" action, less weight gainDavid Mendosa: Benefits of Levemir than other insulins, and less day-to-day variabilityLevemir:Product Details than NPH or Lantus insulins. At an ADA Symposium prior to Levemir's US approval in 2005, Novo Nordisk claimed that if NPH has a patient to patient variability of 60%, Lantus (insulin glargine) then has a 40% variability, and Levemir a 25% rate of variabilityNovo--Less Variability--ADA Symposium. Usage and Handling Levemir comes in 3ml pen cartridges or prefilled 3ml insulin pens in Europe, 10ml vials and 3ml prefilled insulin pens in the United States, and all three forms in Canada. Cartridges, when available, are compatible with all Novo Nordisk insulin pens including the Novopen JuniorNovopen Junior--Levemir Cartridges and Novopen 3 DemiNovopen 3 Demi--Levemir Cartridges, which both allow half-unit doses. Dosages finer than 1/2 unit increments must be dispensed by using a syringe with the cartridge, which is in this case quite easy. Pictorial at link belowSmall Doses From a Cartridge--Using a Syringe Pictorial When the cartridge is part of a disposable pen, you must inject an equal volume of air into the cartridge before drawing insulin, to keep pressure equalized. Also, do not reinsert a cartridge into a refillable pen, or use a disposable pen mechanism, after using it with a syringe, to to avoid stress on the pen mechanism and likely destruction of the cartridge or pen. Levemir's shelf life is 2 years. After first opening the product must be stored, officially for a maximum of 6 weeks, not above 30°C. It may be stored in a refrigerator (2°C - 8°C) not near a freezing compartment. Do not freeze. Protect from lightElectronic Medicines Compendium--EMC-UK. The insulin is clear and does not need rolling or agitation. Pens in use are recommended not to be refrigerated, but stored in a dark cool place below 30°C. (Experienced users have not found problems with refrigerating pens in use, though. Users report longer usage life when refrigerated, up to 6 monthsJock's Levemir lasts 6 months when refrigerated.) Pen cartridges used with a syringe may of course be refrigerated for longer life. Levemir appears to work fine when stored overnight in syringes for prepared dosing. Novo Nordisk themselves have not yet tested diluted Levemir, and so have no consistent answer about whether this is possible. The US web site recommends against it. About mixing with other insulins they say: "If Levemir is mixed with other insulin preparations the profile of action of one or both individual components may change. Mixing Levemir with a rapid-acting insulin analogue like insulin aspart will reduce and delay the maximum effect of the rapid-acting insulin compared to that observed following separate injections."ChildrenWithDiabetes--Mixing Levemir With Other Insulins Availability Levemir is quite new: * was approved for use in Europe in 2003, * by the US FDA in June 2005. * available in Canada since January 2006, * available in the US sinceMarch 28, 2006Novo Press Release--US Availability of Levemir. At this time, the US release does not include 3ml "Penfill" cartridges, which turn out much cheaper for cats and small dogs than 10ml vials, but in vial and FlexPen form only. FlexPens may be used with syringes just as pen cartridges may. Europe and Canada do have cartridges available though! Page 13 of the FDA approval informationFDA Approval Information-Levemir indicates that Novo Nordisk has been assigned NDA numbers (US drug identification coding) for 3mL PenFill cartridges and an InnoLet dosing device, in addition to the vials and FlexPens. This would mean that Levemir may appear in those forms in the US at some point in the future. Instructions on importing cartridges from England to the US are on the FDMB link below FDMB--Ordering Levemir Cartridges From the UK. Importing from Canada may be easier. Veterinary use For vets and prospective new users, please see these few Cases of cats and dogs using Levemir. It's too early to say if Levemir is a good insulin for cats or dogs, but it seems effective in those early cases. This Levemir protocolKirsten and Tilly's Levemir/Lantus protocol was made by one experienced Levemir feline user and works well for others, including feline Lantus users. In the EU testing mentioned above, the 25% efficacy figure at 6nmol/unit in humans was not consistent between species, due to the albumin-binding side-chain physically interfering with insulin receptors, which vary in structure by species. Dogs and pigs found it 100% effective, but in mice and rabbits it was only 1/15 as effective per nmol. (Cats are not mentioned.) According to the tests, therefore, the marketed concentration of 24nmol/unit will seem about normal to humans, 4 times stronger than normal to dogs, and we're not sure about cats. The handful of cats using Levemir so far appear to react to it with the same efficacy as humans, that is, using comparable doses to other human insulins they've used. Here's a full 24h glucose curve in the first known feline case, Jocularity. Notice that Jock's dose (3.25U for 6.5kg) here is higher than those shown in the Novo experiments (0.5 U/kg), and that his peak is close to 11 hours. This is consistent with the shifting peak time shown in the 0.2, 0.3, and 0.4U/kg cases above. But it's consistent with human times, not the usually sped-up feline times. Possible explanation: The protein-binding time-delay action of Levemir is not dependent on the animal's metabolism, or at least not the same part of it that makes other insulins run faster in cats. Notice that except for the rise at the beginning (likely due to slow onset), the curve is nearly symmetrical, gradual on both sides, and lasts 21 hours before returning to previous level. This means it's very easy on the animal both at the beginning and end of its action, and it can easily be overlapped to the next dose without surprises or difficult calculations. Technical details Levemir is a clear solution created by genetically engineered yeast. It is analogous to human insulin, but includes a "fatty acyl side chain" that binds temporarily to albumin (found under the skin and in abundance in blood plasma)(98% albumin-boundInsulin Detemir) and makes the molecule "cling" to the bigger albumin molecules for a while before releasing -- making the molecules slower to enter and exit the bloodstream, and slower to enter the cells. Unlike its long-acting rival Lantus, Levemir's time-delay action occurs in the bloodstream and at the target sites, not only at the subcutaneous injection site, and doesn't depend as much on the properties of the injection site or the suspension (which is Isophane, like NPH and other analog mixed insulins)The Mechanism of Protraction of Insulin Detemir Pharmaceutical Research 2004Is Insulin Detemir Able to Favor a Lower Variability in the Action of Injected Insulin in Diabetic Subjects? Diabetes & Metabolism-2005. Human insulin is altered to produce insulin detemir (Levemir) by omitting the amino acid Threonine at insulin B chain position #30 and attaching a C14 fatty acid chain to the amino acid at position #29, LysineRx List.com-Levemir. The combination of the omission of the threonine amino acid at position #30 on the B insulin chain and the addition of the fatty acid side chain at position B-#29 binds the insulin heavily to albuminUCSD Medical Center-Department of Pharmacy-Insulin Detemir-Page 2. http://www.rxlist.com/cgi/images/levemir1.gif Alterations of human insulin producing insulin detemir (Levemir) Also, the insulin now has more self association tendencies (remaining in hexamer form) than unaltered human insulin. Having the insulin stay in hexamer form longer before breaking down into dimers and monomers means slower absorption, which works out to slower onset, peak and longer duration. Injection sites should be rotated to avoid lipodystrophy, as with any insulin. The good news is, according to Novo Nordisk, Levemir's stretched-out action in the bloodstream makes its absorption less dependent on injection site conditions (and on rotation) than Lantus. This claim is boosted by Novo's findings of lower day-to-day variability on Levemir compared to LantusLevemir vs. Lantus: Day-to-Day Variability. Levemir was tested against NPH/isophane insulin for EU approval. EMEA Scientific Discussion Levemir During the tests, (see page 6) Levemir at usual insulin concentrations (6nmol per unit) was found in humans to have only about 25% of the glucose-lowering action of the same dose of NPHComparison of Levemir & NPH at Normal Insulin Concentrations, so the concentration was increased fourfold to 24 nmol/unit to compensate. The version being marketed has a concentration of 24 nmol/unit, 2400 nmol per mL. Note that this efficacy problem differs between species, see Veterinary use above. Levemir's action profile, according to Novo's Trial NN304-1338, a randomised, double-blind, cross-over trial involving 12 subjects, looks like this: The mean duration of action for Levemir ranges from 5.7 hours at lower dosages to 23.2 hours at the higher ones. For doses in the range of 0.2 to 0.4 U/kg, Levemir exerts more than 50% of its maximum effect from 3-4 hours to approximately 14 hours after being administeredLevemir Peak & Duration Information. An interesting note re: using LevemirLevemir-Insulin Detemir Remedyfind.com is that it can be used in monotherapyDorlands Medical Dictionary-Definition of Monotherapy, meaning the insulin need not necessarily be used in conjunction with bolus insulins or Oral medication. Amino Acid Sequence of Insulin PreparationsPharmacy Times-Guide to Insulin Preparations These are human activity profiles. Further Reading *Mechanism of Protracted Metabolic Effects of Fatty Acid Acylated Insulin, NN304 (Insulin Detemir/Levemir), in Dogs: Retention of NN304 by Albumin Diabetologia 1999 *Medical summary sheet *Cases of cats and dogs using Levemir *Levemir's EU approval testing details *Less variability (Novo Nordisk)Click "I am a healthcare professional". DON'T click "from the US". *Improved Glycemic control (Novo Nordisk)Click "I am a healthcare professional". DON'T click "from the US". *Less weight gain (Novo Nordisk)Click "I am a healthcare professional". DON'T click "from the US". *Powerpoint presentation on variability *US Levemir website *Video: Basal/bolus method, desired vs. practical insulin action, and Levemir mechanism (Novo Nordisk) *How to Achieve a Predictable Basal Insulin? Diabetes & Metabolism 2005 *Insulin Detemir Under Steady-State Conditions: No Accumulation & Constant Metabolic Effect Over Time With Twice-Daily Use in Type 1 Diabetes Diabetic Medicine (UK)-2006 *Insulin Detemir: From Concept to Clinical Experience-Expert Opinion on Pharmacotherapy-2006 References Category:InsulinsCategory:AnalogsCategory:long-actingCategory:Novo Nordisk Category:R-DNA/GE/GMCategory:Rx Status